Antibiotic consumption trends in Ghana: analysis of six-years pharmacy issue data from a secondary healthcare facility

Abstract Background Surveillance of hospital antibiotic consumption provides data to inform corrective action and for monitoring antimicrobial stewardship activities. This study described antibiotic consumption patterns from 2016 through 2021 at a secondary healthcare facility in Ghana. Methods Using the WHO methodology for surveillance of antimicrobial consumption in hospitals, we analysed a 6-year pharmacy issue data at the Eastern Regional Hospital. We report on the defined daily dose (DDD) per 100 patients, types of antibiotics consumed according to Anatomic Therapeutic Classification (ATC), WHO AWaRe classification; trends in antibiotic consumption and expenditure per DDD of antibiotics consumed. Results Over the period, the mean (±standard deviation) antibiotic consumption rate was 256.7 ± 33 DDD/100 patients per year. A linear regression model showed an insignificant decreasing trend in antibiotic consumption (coefficient for time –0.561; P = 0.247). The top three consumed antibiotics in DDD/100 patients at ATC level 5 were amoxicillin-clavulanate (n = 372.6), cefuroxime (n = 287.4) and sulfamethoxazole-trimethoprim (n = 145.8). The yearly Access-to-Watch ratio decreased from 2.4 in 2016 to 1.2 in 2021. The mean yearly cost of antibiotics was $394 206 ± 57 618 US dollars. The top three antibiotics consumed in terms of cost were clindamycin $718 366.3, amoxicillin-clavulanate $650 928.3 and ceftriaxone $283 648.5. Conclusion This study showed a sturdy rate of antibiotic consumption over the 6-year period with a year-on-year decrease in the Access-to-Watch antibiotic ratio. Data from pharmacy drug issues offer an opportunity to conduct antibiotic consumption surveillance at the hospital and national level in Ghana.


Introduction
Globally, there has been a 65% increase in antimicrobial consumption (AMC) in humans between the years 2000 and 2015, with this increase driven mainly by low-and middle-income countries. 1 Increasing antimicrobial use is considered a major driver of antimicrobial resistance (AMR). AMR is considered a global public health problem. 2,3 Several reports from Ghana show increasing AMR, with a high prevalence of resistance phenotypes such as extended-spectrum beta-lactamases and increasing reports of carbapenemaseproducing bacteria. [4][5][6][7] The Ghana national policy and action plan on AMR that is aligned with the global action plan on AMR highlight the need to strengthen surveillance and research as well as optimize the use of antimicrobials. 8 Optimizing antimicrobial use and consumption through antimicrobial stewardship hinges on the availability of antimicrobial use and consumption data. Antimicrobial use and consumption data can provide warning signs concerning antimicrobial exposure and use, allowing for the institution of corrective measures. It may also serve as a monitoring tool for interventions aimed at reducing antimicrobial exposure. 1,9 In Ghana, surveillance of antimicrobial consumption at the hospital and national level is lacking, however, several point prevalence surveys on antimicrobial use have shown 47% to 66% prevalence of antimicrobial use among hospitalized patients. [10][11][12][13] Currently, Ghana is undergoing a national digitalization agenda that includes the provision and use of electronic health records in healthcare facilities. Electronic health records of hospital pharmacies and doctors' prescribing notes represent low-hanging fruit for conducting surveillance of antimicrobial use and consumption at the hospital level in Ghana. The Eastern Regional Hospital (ERH), 14 is a secondary referral facility that provides a range of specialist services for the >2 million people living in rural and urban settings in the Eastern region of Ghana. 15 The hospital has a history of electronic health records use for the past 6 years and has accumulated records useful for conducting antimicrobial consumption studies. These data could provide an understanding of one of the potential drivers of AMR in the hospital and inform antimicrobial stewardship strategies. In this study, we evaluated the antibiotic consumption trends at the ERH from 2016 through 2021 using WHO's defined daily dose (DDD) methodology.

Study design and settings
Using the WHO methodology for the global programme on surveillance of antimicrobial consumption in hospitals, 16,17 we analysed a 6-year pharmacy central pharmacy issues data. The central pharmacy stores of the hospital dispense drugs to pharmacy units associated with various departments of the hospital. The Pharmacy Department distributes drugs using the stock system, where dispensed drugs through the supply chain are recorded. Patients pay for any drugs consumed with cash or through the National Health Insurance System. A recent point prevalence survey conducted at the hospital showed an antimicrobial use prevalence of 50%. 13 The hospital uses the national standard treatment guidelines as the main document supporting antimicrobial prescriptions although other documents such as the British National Formulary are used. 18 The ERH has a microbiology laboratory that routinely performs bacterial cultures and antimicrobial susceptibility testing. The hospital's Information Technology Department manages electronic health records where medical records of patients and pharmacy data are stored.

Antibiotic inclusion criteria
Data summaries on antibiotics dispensed over 71 consecutive months from January 2016 through November 2021 were copied from pharmacy electronic records and transferred to an Excel ™ -based data collection instrument. Data extracted included the antibiotic name, the dosage, route of administration, quantity, date dispensed and the cost of the issued antibiotics. No patient-level information on prescriptions-e.g. indication or age of the patient-was available. Total patient attendance to the hospital for the years under consideration was retrieved. In this study, we included only data on antibiotics for systemic use, classified in the J01 category, by the WHO Anatomic Therapeutic (ATC) classification system. 17 The WHO also recommends categorizing antibiotics as Access, Watch or Reserve (AWaRe), 19,20 and we used the 2021 database 20 to classify them accordingly. Topical antibiotics were excluded from the study. Antimicrobials used for managing tuberculosis, parasites and fungi were not also included.

Calculation of antibiotic consumption rates
Antibiotic consumption was estimated on the basis of the amount dispensed from the central pharmacy store in standard units of milligrams or millilitres. Each standard unit was defined based on a single tablet, capsule, ampoule, vial or liquid preparation for oral consumption. 16 Each antibiotic was assigned to a WHO ATC level 4 and 5 classifications. We then expressed the number of drugs dispensed for each antibiotic class as our consumption data in DDD according to WHO methodology. 16 The DDD is the assumed average maintenance dose per day for a medicine used for its main indication in an adult. It is a globally accepted unit for measuring drug consumption of different strengths or combinations and can be used to compare rates between different antibiotic categories and years. 19,20 The DDD was calculated by converting the total amount of antibiotic dispensed in into grams and divided by the standard WHO ATC DDD value given in grams. When measuring antibiotic consumption in a hospital, where attendance data is available but no patient-level information can be accessed, DDD per 100 patients is the recommended method for standardization. 16 In this study, we used total patients' attendance at ERH to represent the population served by the hospital. This was the closest and best representation of the population served by the hospital, as most in-and outpatients are accounted for in the patient attendance data. The DDD/100 patients were obtained by dividing the calculated total DDD for each year by the patient attendance for the respective year and multiplying the ratio by 100. The expenditure on antibiotic consumption was calculated as expenditure per DDD by multiplying the number of antibiotics issued in a period (e.g. all antibiotics or specific types) and the cost and dividing by the calculated DDD of the antibiotic for that period. For subgroup analysis, we compared yearly variations in antibiotic consumption for drug categories (e.g. AWaRe) by calculating the per cent contribution of that antibiotic category to the overall antibiotic consumption that year.

Data analysis
Data were entered and cleaned using Microsoft Excel ® 2021 and exported to the STATA ® software for descriptive and analytical studies. Continuous variables were presented as means ± standard deviations (SD) and sums. Categorical variables were presented as frequencies and percentages. Difference in antibiotic consumption across the years was determined using Chi-square test, with the Marascuilo's post hoc procedure applied for subsequent pairwise comparisons. The Chi-square trend analysis was used to compare the trend in consumption of WHO AWaRe antibiotic groups over the years. Measures of relative consumption, expressed as a percentage of the total consumption of groups of antibiotics, were derived for each antibiotic. A linear regression model was used to assess the trend of antibiotic consumption rate over time. The coefficient for time and P value for the trend of antibiotic consumption was calculated using yearly measures. All statistical tests were considered significant at a P value <0.05. The cumulative change in consumption for each antibiotic over the study period was calculated by adding the absolute differences in DDD/100 patients between 2017 and 2016, 2018 and 2017, 2019 and 2018, 2020 and 2019, and 2021 and 2020. With regards to the cost of consumed antimicrobial agent in US dollars ($), the amount of antimicrobial agent in Ghana cedi was converted to dollars using the average yearly dollar rate.

Ethical considerations
Ethical clearance for the study was obtained from the Ghana Health Service Ethics Review Committee with protocol number GHS-ERC 004/ 05/22. All data extracted from the EHR were summaries and aggregated data from antimicrobials issued from the pharmacy stores between 2016 and 2021. No individual patient records were collected, thus findings from the study cannot be linked to any patient.

Results
Over the 6-year survey period, we extracted data summaries on 15 different antibiotics at ATC level 4 (yearly mean ± SD, 14.33 ± 0.52) and 26 antibiotics at ATC level 5 (yearly mean ± SD, 24.67 ± 0.82) from the electronic records at ERH for analysis (Table 1). From a total of 26 types of antibiotics issued, 13 were in the Access category, 10 in the Watch category and none were in the Reserve category. The antibiotics were issued to a yearly mean population of 170 044.2 ± 10 878.5 patients attending the hospital. The mean volume in DDD of antibiotics issued per year was 81 839.2 ± 190

Antimicrobial consumption according to AWaRe classifications
Most (63.3%, n = 564.79/975.11) of the antibiotics consumption in DDD/100 patients over the 6 years belonged to the Access group and there was no consumption of Reserve antibiotics over the period of study. Unclassified antibiotics represented 0.026 DDD/100 patients accounting for 0.002% of total consumed antibiotics. Figure 1

Antimicrobial consumption rates by ATC classification
The DDD/100 patients according to ATC level 4 is presented in Figure 2 Table S3.

Cost of antimicrobials consumed
The total cost of antibiotics over the 6 years was

Discussion
Globally, antibiotic consumption has increased over the last two decades, fuelled mainly by consumption in LMICs. 1 Data on antibiotic consumption are critical in informing and evaluating antimicrobial stewardship programmes implemented at the hospital and national levels to combat AMR. This study found an insignificant drop in antibiotic consumption from 2019 to 2021 compared to 2016 to 2018, with the most consumed antimicrobial in the hospital being amoxicillin-clavulanate. Antibiotic consumption in the hospital increased from 2016 to 2018 and decreased sharply between 2019 and 2020 before beginning to rise again in 2021. Whereas the drop in 2020 antibiotic consumption may be attributed to the COVID-19 pandemic and the consequent drop in hospital attendance, it is not easy to fathom the sharp drop in antibiotic consumption in 2019. One possible reason could be stockouts; however, this study did not have access to this data. Amoxicillin-clavulanate and cefuroxime were the two commonest antibiotics consumed in the hospital over the study period. Similarly, these agents have been documented as part of the top five antibiotics used in hospitalized patients from previous point prevalence surveys in Ghana. 10,13 These antibiotics are recommended for the treatment of upper and lower respiratory tract and urinary tract infections by the Standard Treatment Guidelines of Ghana, 18 and they are on the national health insurance of Ghana's list of drugs, 21 so are not prohibited by out-of-pocket cost. On the contrary, agents like ceftriaxone which feature prominently as part of the top five antibiotics used in most point prevalence surveys in Ghana was the tenth most consumed antibiotic in this study. 10,13 Also, there was sharp rise in the consumption of azithromycin in 2021. This could be due to increased use as a result of speculations that suggested azithromycin as an agent for treating COVID-19. This highlights the important role of antibiotic consumption surveillance or studies in its ability to give a complete antibiotic utilization picture compared to point prevalence surveys. It is of interest to note, however, that other antibiotics such as clindamycin and ceftriaxone were responsible for the first and third antibiotics when expenditure was assessed.
Overall, most antibiotics prescribed belonged to the Access group of antibiotics, however, the proportion of Watch antibiotics consumed yearly increased from 2016 to 2021 and is exemplified by a decreasing Access-to-Watch index from 2.4 in 2016 to 1.2 in 2021. This means that as of 2021 antibiotic consumption in the hospital did not conform to the WHO target, which requires at least 60% of overall antibiotic consumption to be made of the Access group of antibiotics. 20 This rise in Watch antibiotic use relative to the Access group of antibiotics is similar to global findings especially those from lower-and middle-income countries (LMICs) and may be a reflection of increasing antibiotic resistance observed in the study setting as has been suggested elsewhere. 22 Increasing the use of Watch antibiotics could also be attributed to improved economic status in many LMICs with an associated increased purchasing power for more expensive broad-spectrum antibiotics, 1 and uncertainty concerning febrile illness diagnosis. 23 There was no consumption of reserve antibiotics in the hospital over the study period, this may be a result of their unavailability on the local market, absence in the Standard Treatment Guidelines of Ghana 18 and the fact that they are not funded by the health insurance scheme 21 . Similar absent use of reserve antibiotics has been documented in point prevalence surveys among hospitalized patients in Ghana. 10,13,24,25 This study has potential limitations. First, the study is limited to one secondary healthcare facility thus finding may not be generalizable to other healthcare settings. Second, the data could not be segregated into outpatient and inpatient status that would have been useful to show any differences in antibiotic consumption patterns. However, our data showed that 90% of antibiotics were oral formulations, which suggests that a large proportion of consumed antibiotics was prescribed to outpatients. Antibiotic consumption data for 2021 was short by 1 month due to a change in EHR at the hospital, and this may have affected the overall antibiotic consumption observed especially for that year. The level of antibiotic resistance in the population under study is unknown and this could have given better meaning to the observed antibiotic consumption. Also, the findings in this study are not commensurate with the appropriateness of use. This study used hospital antibiotics issue data that are dependent on the medications stocked by the hospital and did not account for medications that were prescribed and purchased in pharmacies outside the hospital for use in the hospital by individual patients.
This could explain the lack of data on reserve antibiotics that were not stocked by the hospital. Also, the data collected did not account for stockouts that could have affected consumption levels. However, findings from this study are useful because it is one of the first to describe hospital-wide antibiotic consumption in Ghana and describes the potential use of drug issuance data as a measure of hospital-level antibiotic consumption. These data could serve as baseline data for future studies and antibiotic stewardship initiatives.
This study has the following policy implications. First, data from pharmacy drug issues may be a useful resource for conducting antibiotic consumption surveillance at the hospital and national level and may represent low-hanging fruit for consumption surveillance in Ghana considering the EHR rollout across healthcare facilities. Second, there is a need to understand the reasons behind the decreasing Access-to-Watch ratio observed in this study through the conduct of further studies. This will be important in influencing deliberate policies aimed at reversing the trend towards >60% prescription of antibiotics in the hospital belonging to the Access group. 20 Third, there is also the need to strengthen AMR surveillance activities at the hospital to monitor the impact of the increase in the use of Watch antibiotics.

Conclusion
This study showed a sturdy rate of antibiotic consumption over the 6-year study period with a year-on-year decrease in the Access-to-Watch ratio of antibiotics. Amoxicillin-clavulanate, cefuroxime and sulfamethoxazole-trimethoprim were the three most consumed antibiotics; however, clindamycin, amoxicillinclavulanate and ceftriaxone were the top three antibiotics according to the total budget spent. Data from pharmacy drug issues offer an opportunity to conduct antibiotic surveillance at the hospital level in Ghana and when aggregated may give a national picture. This could be a useful resource for monitoring antibiotic stewardship activities at the hospital and national levels.

Availability of data
The data for this study are available upon reasonable request from the corresponding author.

Supplementary data
Tables S1 to S3 are available as Supplementary data at JAC Online.